A gene variant thought to play a role in the pathology of Alzheimer's disease is also associated with other forms of dementia, researchers reported.

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Lewy body disease refers to a spectrum of clinicopathologic entities that include Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Dementia with Lewy bodies and Parkinson's disease with dementia are differentiated from one another using clinical criteria.

In this study, a variant gene thought to play a role in Alzheimer's disease, the ε4 allele of the gene for apolipoprotein E, was elevated in both Parkinson's and Lewy body dementia.

A gene variant thought to play a role in the pathology of Alzheimer's disease is also associated with other forms of dementia, researchers reported.

In a genetic case-control study, the variant – the ε4 allele of the gene for apolipoprotein E (APOE) – was elevated in both Parkinson's and Lewy body dementia, according to Cyrus Zabetian, MD, of the VA Puget Sound Health Care System in Seattle, and colleagues.

The surprising findings suggest that APOE ε4 can contribute to neurodegeneration through mechanisms distinct from the disturbed amyloid processing found in Alzheimer's, Zabetian and colleagues argued online in Archives of Neurology.

Lewy body disease includes Parkinson's, Parkinson's with dementia, and dementia with Lewy bodies, which are distinguished on the basis of clinical criteria, the researchers noted.

If dementia is diagnosed before or at the same time as parkinsonism, the illness is referred to as dementia with Lewy bodies, while if the parkinsonism comes at least a year before dementia, it is referred to as Parkinson's dementia.

But the classifications are complicated – in some cases neuropathologic changes characteristic of Lewy body disease co-exist with those of Alzheimer's.

For this analysis, the researchers defined four types of dementia – Alzheimer's without Lewy body neuropathologic changes, Lewy body disease with Alzheimer's features, pure Lewy body disease (with low or no Alzheimer's features), and Parkinson's dementia (also with low or no Alzheimer's features).

They conducted genetic analysis on autopsy to pin down the frequency of APOE ε4 in each group, as well as in cognitively normal controls.

All told, they analyzed the genetics of 244 people with Alzheimer's, 224 with Lewy body/Alzheimer's, 91 with pure Lewy body disease, and 81 with Parkinson's dementia. Results were compared with those from 269 controls.

Zabetian and colleagues found that, as expected, the frequency of the allele was higher in those with Alzheimer's or Alzheimer's features than among controls -- 38.1% and 40.6%, respectively, versus 7.2%.

The differences were significant at P=1.97 x 10−32 and P=1.65 x 10−35, respectively.

But, unexpectedly, the rates were also higher in the other two groups -- 31.9% in pure Lewy body disease and 19.1% in Parkinson's dementia.

The differences were significant at P=1.2 x 10−16 and P=1.94 x 10−5, respectively.

And the difference between the latter two groups was significant at P=0.01.

In a logistic regression adjusted for age and sex, using the controls as the reference group, the ε4 allele was strongly associated with all four forms of dementia. The odds ratio was:

9.9 with a 95% confidence interval from 6.4 to 15.3 for Alzheimer's

12.6 with a 95% confidence interval from 8.1 to 19.8 for Lewy body disease with Alzheimer's features

6.1 with a 95% confidence interval from 3.5 to 10.5 for pure Lewy body disease

3.1 with a 95% confidence interval from 1.7 to 5.6 for Parkinson's dementia

Previous research has linked APOE ε4 to the accumulation of amyloid beta in patients with Alzheimer's, but the current study suggests it might play other roles in neurodegeneration, the researchers argued.

Zabetian and colleagues cautioned that, while the sample was limited to whites, they did not have genetic data on ancestry and so "cannot entirely exclude the possibility of unrecognized population structure" in the data.

The study was supported by the Department of Veterans Affairs and the NIH.

Zabetian made no disclosures.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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